1. Field of the Invention
The present invention relates to novel complexes of major histocompability complex (MHC) molecules and uses of such complexes. More particularly, the invention relates to MHC fusion complexes that contain a MHC molecule with a peptide-binding groove and a presenting peptide covalently linked to the MHC protein. Fusion complexes of the invention are useful for a variety of applications including in vitro screens for identification and isolation of peptides that modulate activity of selected T cells, including peptides that are T cell receptor antagonists and partial agonists, methods of suppressing an immune response of a mammal and methods for inducing an immune response in a mammal.
2. Background
Antigen-specific T cell responses are invoked by antigenic peptides bound to the binding groove or cleft of major histocompatibility complex (MHC) glycoproteins as part of the mechanism of the immune system to identify and respond to foreign antigens. The bound antigenic peptides interact with T cell receptors and thereby modulate an immune response. The antigenic peptides are bound by non-covalent means to particular “binding pockets” comprised of polymorphic residues of the MHC protein's binding groove.
MHC class II molecules are heterodimeric glycoproteins consisting of α and β chains. The α1 and β1 domains of these molecules fold together to form a peptide binding grove. Antigenic peptides bind the MHC molecule through interaction between anchor amino acids on the peptide and the α1 and β1 domains. Crystal structure of human class II HLA-DR1 complex with an influenza virus peptide indicate that the N- and C-terminal ends of the bound peptide extend out of the binding groove such that the C-terminus of the peptide is proximal to the N-terminus of the β chain [Brown, J. H. et al. (1993) Nature 364: 33–39; Stern, L. J. et al. (1994) Nature 368: 215–221]. MHC class I molecules have different domain organizations than MHC class II molecules, but generally similar structure with a peptide binding site or groove that is distal to membrane domains [see, e.g., Rudensky, A. Y. et al., (1991) Nature 353:622–626]. See also U.S. Pat. Nos. 5,284,935; 5,260,422; 5,194,425; 5,130,297; and WO 92/18150 and WO 93/10220 for discussions of MHC molecules.
MHC molecules complexed with antigenic peptides can induce selective immunosuppression by several different mechanisms [see, e.g., Guery, J. et al. (1993) Critical Reviews in Immunology 13(3/4): 195–206].
More specifically, it has been reported that peptide-MHC complexes on the surface of antigen presenting cells will only induce clonal expansion of a T cell line specific for the MHC bound peptide if the antigen presenting cells also deliver co-stimulatory signals. One proposed approach takes advantage of this requirement for T cell activation and inhibits T cell development by interaction with the antigenic peptide bound to the MHC molecule in the absence of co-stimulatory signals. See Nicolle, M. et al., J. Clin. Invest. (1994) 93: 1361–1369; and Sharma, S., et al., Proc. Natl. Acad. Sci. USA (1991) 88: 11465–11469.
Another proposed approach inhibits T cell development with MHC molecules that contain a bound peptide that is an antagonist or partial agonist to a T cell receptor (TcR). See Evavold, B. et al., Immunology Today (1993) 14(12): 602–609.
Modifications of the antigenic peptides bound to T cell receptors have been attempted to examine residues responsible for specific T cell responses. Determination of such “activating” amino acids of the antigenic peptides could provide insight of suitable sequence of a TcR partial agonist or antagonist. See Evavold, B. et al., supra.
It also has been speculated that new vaccines might be developed based on determination of the nature of various antigenic peptides bound to MHC molecules. See Chicz, R., et al., Immunology Today (1994) 15(4): 155–160.
It thus would be desirable to have MHC molecules that contain an antigenic peptide for modulation of the activity of a T cell receptor. It also would be desirable to have a means for preparation of MHC molecules with virtually any desired peptide positioned in a binding groove for interaction with a T cell receptor. It would be further desirable to have a means to identify peptides that are capable of modulating the activity of a T cell receptor.